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Sick and tired of being sick and tired
April 2013
by Amy Swinderman  |  Email the author


NEW YORK—Boosted by a $1.9-million grant from the U.S. National Institute of Mental Health, a multidisciplinary clinical research effort seeks to discover novel biomarkers in patients with chronic fatigue syndrome (CFS), which would represent a major paradigm shift in the criteria used to diagnose patients with what has been called a "medically mysterious" illness.
A four-year, innovative study to be conducted by Weill Cornell Medical College, the Icahn School of Medicine at Mount Sinai and Beth Israel Medical Center aims to expand the scientific understanding of CFS and improve diagnostics for the condition—which eventually may lead to the identification of new and more effective treatment targets.  
A complex, multisystem disorder, CFS is often misdiagnosed, misunderstood and mistreated. National health organizations have estimated more than 1 million Americans and approximately a quarter of a million people in the United Kingdom have CFS. Diagnosing CFS is as serious a problem as prevalence of the condition. The "official," or most widely used, diagnostic criteria for CFS come from the 1994 research guidelines proposed by the International Chronic Fatigue Syndrome Study Group, which was led by the Centers for Disease Control and Prevention (CDC). The CDC criteria specifies that the following basic conditions must be met: that the condition is of new or definite onset (has not been lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social or personal activities.
Differentiation of CFS and neuropsychiatric illnesses, such as major depressive disorder (MDD), can be daunting and is a continuing challenge, notes Dr. Dikoma Shungu, a professor of physics in radiology and chief of the Laboratory for Advanced Magnetic Resonance Spectroscopy Research at Weill Cornell Medical College—and a principal investigator of the study.
"Right now, a diagnosis of CFS is a diagnosis by exclusion," Shungu says. "The million-dollar question is: how do you differ CFS from other co-morbid diseases? For example, a lot of people with CFS show signs of depression, anxiety or pain. It 's very difficult to define, and has very different causes in different patients."  
Because of these challenges, research funding for CFS has been historically limited, Shungu notes.
"A lot of physicians don't believe that CFS is a distinct disease from depression. If you don't believe that something is a real disease, people are reluctant to invest money in research," he says. "This large, generous NIH award will allow us to accelerate in-depth, novel clinical research for CFS to make the significant strides we vitally need for research discovery and clinical care."  
The grant will be used to advance seven years of research conducted by the partnering institutions. Using neuroimaging and a battery of clinical tests, a pilot study suggested that the key culprit in CFS may be increased and sustained oxidative stress. Levels of cortical glutathione (GSH)—the most abundant and one of the most important antioxidants in living tissue—decreased by 36 percent in CFS patients. This novel cortical GSH deficit finding was also correlated with those patients with increased levels of blood markers of oxidative stress and symptoms of CFS. Study results also show CFS patients have significantly elevated ventricular cerebrospinal fluid lactate and decreased regional cerebral blood flow.  
However, because the researchers also found in their pilot study that the abnormalities identified in CFS patients were similar to the abnormalities witnessed in patients with MDD, the researchers hope to give validity to the oxidative stress hypothesis, but they must first distinguish between the two conditions.  
"The reason these disorders probably overlap so much is because they have the same biological abnormalities," says Shungu. "What we need to do is not treat MDD or CFS as distinct entities, but to find drugs for different sub-groups of CFS and MDD, and focus on them."

Shungu clarifies that neither CFS nor MDD are distinct entities within their respective disease categories.

"That is, MDD is not one clean disease entity because it is highly heterogeneous; there is treatment-resistant depression, atypical depression, depression with melancholic or anhedonic features. This heterogeneity needs to be considered, and we need to not treat 'depression' as just one thing," he explains.

The same holds true for CFS, which is known to be highly heterogeneous, even in its mode of onset, he adds.

"CFS has rheumatologic, infectious or psychiatric features that need to be sorted out in order to really begin to know what CFS is," Shungu says. "I suspect that we will find that CFS consists of different subtypes. It could then be that each subtype of CFS may be diagnosed by specific biomarkers or respond a specific treatment. The implication is not that MDD and CFS are not distinct medical entities. Our primary hypothesis, in fact, is that they are distinct. However, to achieve a clearer distinction, which our research is designed to accomplish, will require that we look at subtypes of both CFS and MDD to minimize their inherent heterogeneity, which might also minimize the overlap of their symptoms."
For this study, the researchers plan to enroll 40 patients with CFS, 40 MDD patients and 20 healthy controls. Beth Israel will evaluate and enroll patients in the study. Mount Sinai will screen and characterize the people with depression, and all of the actual measurements will be done at Weill Cornell.
"We will do a spinal tap to look at abnormalities in the cerebral spinal fluid biochemically, rather than doing imaging," says Shungu.
Ultimately, the discovery of specific biomarkers that can differentiate CFS from similarly presenting psychiatric disorders will have a profound impact for how the disorder is perceived, managed, diagnosed and for the development of objective diagnostic tests, therapeutic targets and advanced scientific understanding of this debilitating illness, he says. Shungu adds that the researchers may also apply some of what is learned for other related diseases like fibromyalgia, another chronic pain condition that is difficult to diagnose and treat.
"We must find objective biomarkers for these diseases. When you have biomarkers, people don't argue," he concludes.  
Other study investigators include Dr. Benjamin Natelson of Beth Israel and Dr. Dan Iosifescu of Mount Sinai.
Code: E041323



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